Tumor response, a binary variable, has historically been the main measure of antitumor activity for many cancer phase II single-arm trials. Simon two-stage designs are often used. Sargent et al. proposed a three-outcome trial design in this setting which requires smaller sample sizes. For many new, molecularly targeted therapies, however, tumor response may not be the most reliable endpoint for measuring anti-tumor activity. Increasingly, time-to-event endpoints, such as progression-free survival (PFS), are used in the phase II setting. When such endpoints are the primary measure of efficacy, a randomized concurrently controlled study design is usually required. Given limited resources for phase II, studies are often underpowered with relatively large type I and II error rates, and it is sometimes unavoidable to have a "gray" decision zone after phase II where a clear decision regarding further development actions cannot be made without additional information. Compared with an underpowered standard two-outcome study, a three-outcome design prompts clinical trialists to contemplate the likelihood of landing in the "gray" zone at the trial design stage and choose study design parameters more appropriately. We propose a three-outcome design, with or without interim analyses, for randomized comparative phase II trials when a time-to-event endpoint is used.

翻译：肿瘤反应作为二元变量，历来是许多II期癌症单臂试验评估抗肿瘤活性的主要指标，此时常采用Simon两阶段设计。Sargent等人曾在此背景下提出一种三结局试验设计，该设计所需样本量更小。然而，对于许多新型分子靶向疗法而言，肿瘤反应可能并非衡量抗肿瘤活性的最可靠终点。在II期试验中，无进展生存期（PFS）等时序终点正日益得到应用。当此类终点作为主要疗效指标时，通常需要采用随机化同期对照研究设计。鉴于II期试验资源有限，研究常面临检验效能不足的问题，导致I类和II类错误率相对较高，且有时在II期试验后不可避免地出现“灰色”决策区——即缺乏额外信息时无法就后续研发行动作出明确决策。与检验效能不足的标准双结局研究相比，三结局设计促使临床试验设计者在试验规划阶段即考量落入“灰色”区的可能性，从而更合理地选择研究设计参数。本文针对采用时序终点的随机化比较性II期试验，提出一种包含或不包含期中分析的三结局设计方案。